{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:05:34Z","timestamp":1790672734690,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Azacitidine is a rare triazine\u2010containing nucleoside and a clinically used DNA methyltransferase inhibitor for the treatment of myelodysplastic syndromes. Despite its medical importance, its biosynthetic pathway has remained elusive. Herein, we identified the azacitidine biosynthetic gene cluster (\n                    <jats:italic>aza<\/jats:italic>\n                    BGC) from\n                    <jats:italic>Streptomyces mobaraensis<\/jats:italic>\n                    IPIO2 using a resistance gene\u2010guided comparative genomics strategy and elucidated its biosynthetic pathway via in vivo and in vitro studies. Unexpectedly, the bifunctional GTP cyclohydrolase I AzaE generates the triaminopyrimidine intermediate as the major product and H2NTP as a shunt product from GTP, diverging from canonical GCHI enzymes. The cofactor\u2010independent cupin dioxygenase AzaA then assembles the 1,3,5\u2010triazine scaffold using both O\n                    <jats:sub>2<\/jats:sub>\n                    and H\n                    <jats:sub>2<\/jats:sub>\n                    O as oxygen donors, a mechanism unprecedented in nucleoside antibiotic biosynthesis. Subsequent decarboxylation by AzaB\/AzaC, phosphoribosyl transfer by AzaD, and dephosphorylation by AzaG together with other endogenous hydrolases yield azacitidine. This work uncovers a distinct biosynthetic logic for triazine\u2010containing nucleosides and provides a molecular basis for the synthetic biology\u2010driven production of azacitidine.\n                  <\/jats:p>","DOI":"10.1002\/anie.1881662","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:32:53Z","timestamp":1790670773000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unveiling the Complete Biosynthetic Pathway of Azacitidine: A Rare 1,3,5\u2010Triazine Nucleoside Derived From GTP"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3261-9428","authenticated-orcid":false,"given":"Dan","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7753-0738","authenticated-orcid":false,"given":"Qingxu","family":"Meng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1209-1400","authenticated-orcid":false,"given":"Lingqi","family":"Hua","sequence":"additional","affiliation":[{"name":"College of Life Science Tarim University  Alar Xinjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0669-1963","authenticated-orcid":false,"given":"Mengjun","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4894-0056","authenticated-orcid":false,"given":"Qianjin","family":"Kang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-208X","authenticated-orcid":false,"given":"Min\u2010Juan","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3269-9747","authenticated-orcid":false,"given":"Linquan","family":"Bai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai China"},{"name":"College of Life Science Tarim University  Alar Xinjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2013.794222"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201026258\u2010z"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1698"},{"key":"e_1_2_8_5_1","first-page":"619","article-title":"Microbiological Production of 5\u2010Azacytidine. 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